Brews, fuels, and opioids: Expanding the yeast Ehrlich pathway for chemical and pharmaceutical manufacturing

The Ehrlich pathway is a catabolic process that imparts Saccharomyces cerevisiae and other yeasts with the ability to utilize branched-chain and aromatic amino acids as a source of nitrogen. Using this route, amino acids are transaminated to α-keto acids and the liberated ammonia is utilized for assimilatory reactions. This process leaves behind an array of aliphatic and aromatic carbon skeletons (fusel metabolites) that have found a multitude of uses in the production of flavors, chemicals, and pharmaceuticals. This review provides an update on the genetics and biochemistry of the Ehrlich pathway with an emphasis on the biotechnological valorization of fusel metabolites. We outline the impact of fusel metabolism on the organoleptic properties of fermented beverages and recap ongoing efforts to repurpose the Ehrlich pathway for production of advanced biofuels. We also highlight recent activity directed at producing opioids and other plant benzylisoquinolines, as well as engineering new-to-nature alkaloids by rewiring the yeast Ehrlich pathway. Collectively, these efforts have stimulated a deeper understanding of yeast fusel metabolism and opened new opportunities for biomanufacturing using conventional and non-conventional yeasts.